CHEM 210

Synthesis of 1,4-di-t-butyl-2,5-dimethoxybenzene
(Exp.10)
Synthesis of Acetanilide (Exp.11)

Nucleophilic Acyl Substitution

Synthesis of 1,4-di-t-butyl-2,5-dimethoxybenzene (Exp. 10)
Synthesis of Acetanilide (Exp. 11)

Lecture Outline
1. Purpose of the Experiment
2. Electrophilic Aromatic Substitution
Reactions
3. Friedel-Crafts Alkylation of Benzene
4. Carboxylic Acid Derivatives and
Nucleophilic Acyl Substitution Reactions
5. Synthesis of Amides
6. Procedures
7. Green Chemistry
 Purpose
Part 1
1. To synthesize 1,4-di-t-butyl-2,5-dimethoxybenzene from
1,4-dimethoxybenzene and t-butanol by Friedel-Crafts
Alkylation of the benzene ring.
2. To isolate and purify the product.
3. To determine its m.p and calculate the percent yield.

Part II
1. To synthesize Acetanilide from aniline and acetic acid by
nucleophilic acyl substitution.
2. To isolate and purify the product.
3. To determine its m.p and calculate the percent yield.
 Part 1
Synthesis of 1,4-di-t-butyl-2,5-dimethoxybenzene from
1,4-dimethoxybenzene and t-butanol by Friedel-Crafts
Alkylation of the benzene ring

Friedel-Crafts Alkylation is an electrophilic aromatic

substitution reaction.
 Electrophilic Aromatic Substitution Reaction
H + – E
+E Y +H Y

General mechanism:

Electrophilic aromatic substitutions include:

Nitration, Sulfonation, Halogenation, Friedel-Crafts Alkylation,
and Friedel-Crafts Acylation
 Substituent Effect in Electrophilic Aromatic
Substitution Reactions

Generalizations:
1. All activating substituents are ortho-para directors.

2. Halogen substituents are slightly deactivating but

ortho-para directing.

3. Deactivating substituents are meta directors.

Summary of Substituent Effects in Aromatic Rings
 Friedel-Crafts Alkylation of Benzene
Reaction equation:

Mechanism of formation on the electrophile:

The electrophile is a carbocation formed by the reaction of

an alkyl halide with aluminum chloride a Lewis acid.
 Mechanism of Friedel-Crafts Alkylation

Step 1. Addition of the electrophile.

Step 2. Deprotonation.
 Mechanism of Friedel-Crafts Alkylation
Primary and methyl cations are too unstable to be formed so
the Lewis acid-base complex is the effective electrophile.
 Friedel-Crafts Alkylation and Rearrangements

Rearrangements occur especially with primary alkyl halides.

The electrophile is formed by hydride migration to form a more

stable cation.
 Alternative Sources for Carbocations

Any reaction that generates a carbocation can be used to

produce the electrophile, e.g. protonation of an alkene:

This provides an industrial synthesis of styrene:

 Limitations of Friedel-Crafts

• Reaction fails if benzene has a substituent that is more

deactivating than halogen.

• Carbocations rearrange.
For example, reaction of benzene with n-propyl chloride and
AlCl3 produces isopropylbenzene.

• The alkylbenzene product is more reactive than benzene, so

polyalkylation occurs.
Part 1. Synthesis of 1,4-di-t-butyl-2,5-dimethoxybenene

 The electrophile of this reaction is a carbocation, generated by treating a

tertiary alcohol with a strong acid (H2SO4) as the dehydrating agent.
 The advantage of this method for generating the electrophile is that the tertiary
butyl cation is a stable carbocation and does not rearrange.
 methoxy group is an activating ortho-para director; in this reaction the ring is
dialkylated.
 Polyalkylation occurs because alkylation increases the nucleophilicity of the
ring, increasing the reactivity of the system.
Mechanism for the formation of
1,4-di-tert-butyl-2,5-dimethoxybenzene
 Procedure Part 1
 Weigh 2 g of 1,4-dimethoxybenzene (hydroquinone dimethyl ether), and
transfer it to a 125 mL Erlenmeyer flask
 Add 3.5 mL of t-butyl alcohol and 10 mL of acetic acid
 Shake the solution well until all the solid dissolves
 Put the flask in an ice-water bath to cool to around 5 ºC.
 Measure, using the 100 mL graduated cylinder, very carefully, 10 mL of
concentrated sulfuric acid into a 50 mL Erlenmeyer flask, and cool in a 250
ml beaker filled with ice to cool to 5oC.
 Add a very small portion of the chilled sulfuric acid to the reaction mixture
in the ice bath and stir for a few seconds.
 Check the temperature of the mixture, which increases after the addition
of the acid. Do not let the temperature increase to more than 15ºC, or
else, cool the solution to around 12ºC before adding another portion of
the sulfuric acid. (Keep the sulfuric acid in ice after every addition).
 Procedure Part 1
 Continue this process of addition until you add all the sulfuric acid. You will
observe a yellowish solid formation after the addition of around 7 mL of the
acid.
 Maintain the temperature of the mixture at about 20-25oC for 5 min and then
add, slowly and in portions, ice water to the mixture to dilute the sulfuric acid
to a volume of about 120 mL.
 Stir the solution with a rod to break any solid lumps (the yellowish solid will
turn to white).
 Collect the product on Buchner funnel with suction applying only very gentle
suction at first to avoid breaking the filter paper, which is weakened by the
strong sulfuric acid solution. Then turn on the suction to full force.
 Rinse the flask with a small amount of ice cold water and filter.
 Press down gently on the filter cake with a spatula and let drain well.
 Transfer your solid to an Erlenmeyer flask and crystallize from ethanol.
 Filter your product by suction and let the crystals vacuum dry for 8-10
minutes.
 Weigh the product and calculate percent yield.
 Determine the melting point of your product.
 Part II

Synthesis of Acetanilide from aniline and acetic acid

by nucleophilic acyl substitution.

Acetanilide is an amide and amide are carboxylic acid

derivatives
 Carboxylic Acid Derivatives

Acyl chloride Acid anhydride Ester Amide

Characteristic reaction: Nucleophilic acyl substitution

Nucleophilic acyl
substitution

The mechanism involves an addition step followed by elimination

Structure and Reactivity
 Synthesis of Amides

Synthesis from acid chlorides, acid anhydrides, and esters.

 Part II. Synthesis of Acetanilide
Synthesis of acetanilide is commonly performed using acetic anhydride

Acetic anhydride, pyridine and methylene chloride are hazardous materials.

An alternative method is performed using acetic acid in the presence of zinc

dust as a catalyst. This method is preferable as it applies some of the
principles of green chemistry
 Mechanism of the Reaction

 The reaction between aniline and acetic acid is very slow and
would lead to the formation of the anilinium salt; an acid-
base reaction.
 In the presence of zinc, acetic acid is converted to zinc acetate
which reacts with aniline to form the amide as follows
Mechanism of the Reaction
 Principles of Green Chemistry
Green Chemistry is defined as invention, design, development and
application of chemical products and processes to reduce or to eliminate the
use and generation of substances hazardous to human health and
environment.
The twelve principles of green chemistry are:
1. Prevention. Preventing waste is better than treating or cleaning up waste
after it is created.
2. Atom economy Synthetic methods should try to maximize the incorporation
of all materials used in the process into the final product.
3. Less hazardous chemical syntheses. Synthetic methods should avoid using
or generating substances toxic to humans and/or the environment.
4. Designing safer chemicals. Chemical products should be designed to achieve
their desired function while being as non-toxic as possible.
5. Safer solvents and auxiliaries. Auxiliary substances should be avoided
wherever possible, and as non-hazardous as possible when they must be used.
6. Design for energy efficiency. Energy requirements should be minimized, and
processes should be conduced at ambient temperature and pressure whenever
possible.
7. Use of renewable feedstocks. Whenever it is practical to do so, renewable
feedstocks or raw materials are preferable to non-renewable ones.
8. Reduce derivatives. Unnecessary generation of derivatives—such as the use
of protecting groups—should be minimized or avoided if possible; such steps require
additional reagents and may generate additional waste.
9. Catalysis. Catalytic reagents that can be used in small quantities to repeat a
reaction are superior to stoichiometric reagents (ones that are consumed in a
reaction).
10. Design for degradation. Chemical products should be designed so that they do
not pollute the environment; when their function is complete, they should break
down into non-harmful products.
11. Real-time analysis for pollution prevention. Analytical methodologies need to be
further developed to permit real-time, in-process monitoring and
control before hazardous substances form.
12. Inherently safer chemistry for accident prevention. Whenever possible, the
substances in a process, and the forms of those substances, should be chosen to
minimize risks such as explosions, fires, and accidental releases.
P. Anastas and J. C. Warner, Green Chemistry: Theory and Practice; Oxford
Science Publications, Oxford, 1998
 Procedure Part 2
• Measure 5 mL of aniline and transfer it to a clean and dry pre-weighed
100 mL round bottom flask. Measure the mass of aniline.
• Weigh 0.25 g of zinc dust and transfer it to the same round bottom flask.
• Add 15 mL of glacial acetic acid, a few boiling chips and reflux for 1
hour. (During reflux a clear transparent, or very pale yellow, solution is
observed).
• When 10 minutes are left, measure 50 mL of distilled water in a 100 mL
beaker and cool it in ice.
• Stop heating and let the solution to cool down for a few minutes (not to
room temperature) and then pour the reaction mixture on top of the
cold water while keeping the beaker in ice and stirring with a rod
(almost all the solution will turn to solid). Keep the beaker in ice for 15
minutes and then filter the crystals.
• Wash the product with cold water (two 5 mL portions).
• Crystallize in boiling water using charcoal (during crystallization, when
everything dissolves in the hot solvent, add around 0.2 g (tip of scopula)
decolorizing charcoal.
• Cool in ice and filter by suction.
• Leave to dry till the following week or dry in the oven set at 75ºC for 20
minutes
• Weigh the product and Calculate % yield
• Determine its melting point.